Dose-response relationship between tissue concentrations of UC781 and explant infectibility with HIV type 1 in the RMP-01 rectal safety study.

Abstract

A retrospective correlational analysis of UC781 (0.1, 0.25%) gel pharmacokinetics (PK) and pharmacodynamics (PD) was undertaken using data generated in the RMP-01/MTN-006 Phase 1 rectal safety study of the UC781 microbicide gel, where strong UC781-related inhibition of ex vivo biopsy infectibility (PD) was seen. Precision analysis, linear and logistical correlational methods were applied to model the dose-response relationship. Four analyses of explant virus growth were compared to determine tissue concentrations of UC781 needed to maintain ex vivo virus growth below a range of cut-points. SOFT, a cross-sectional index from a growth curve, and cumulative p24 endpoints were the most precise measurement of ex vivo HIV infection and significantly (p<0.01) correlated with rectal tissue UC781 concentrations. Cut-points reflecting infectibility, ranging from 200 to 1300 p24 pg/ml, provided EC(50,90,95) tissue levels of UC781. A cut-point of 200 p24 pg/ml provided an EC(50) of 2148 UC781 ng/g tissue; a cut-point of 1100 p24 predicted a lower EC(50) of 101 UC781 ng/g. A 30- to 170-fold EC(90):EC(50) ratio was found. Higher p24 cut-points provided more predictive models. Tissue UC781 levels and ex vivo infectibility data were correlated to model dose-response drug efficacy in this small Phase 1 trial. Logistic regression analyses showed EC(50,90,95) values were inversely related to p24 cut-point levels, providing clinically relevant insights into tissue drug concentration necessary for ex vivo suppression of HIV tissue infectibility. This first PK-PD assessment of topical microbicides demonstrates feasibility in Phase 1 trials, enabling comparisons of microbicide efficacy (i.e., EC(50,90,95)) between formulations, compartments, and application methods. (ClinicalTrials.gov; #NCT00408538).

• Authors: Nicola Richardson-Harman, Christine Mauck, Ian McGowan, Peter Anton
• Journal: AIDS research and human retroviruses (AIDS Res Hum Retroviruses) Vol. 28 Issue 11 Pg. 1422-33 (Nov 2012) ISSN: 1931-8405 [Electronic] United States
• PMID: 22900504 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Anilides
• Anti-Infective Agents
• Anti-Infective Agents, Local
• Furans
• Gels
• Thioamides
• UC-781

Topics

• Administration, Rectal
• Analysis of Variance
• Anilides (pharmacology)
• Anti-Infective Agents (pharmacology)
• Anti-Infective Agents, Local (pharmacology)
• Dose-Response Relationship, Drug
• Endoscopy
• Female
• Furans (pharmacology)
• Gels
• HIV Infections (drug therapy, pathology)
• HIV-1 (drug effects)
• Humans
• Logistic Models
• Male
• Rectum (drug effects, pathology, virology)
• Reproducibility of Results
• Retrospective Studies
• Thioamides
• Time Factors
• Tissue Culture Techniques